1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl) piperazine and pharmaceutically acceptable salts and solvents thereof

ABSTRACT

The present invention provides a compound of the formula (I), and the pharmaceutically acceptable salts and solvates thereof, which is useful for treating bladder over-activity or urinary incontinence.

BACKGROUND OF THE INVENTION

[0001] Bladder over-activity and urinary incontinence are commonconditions that present various symptoms that are at best embarrassingand at worst disabling. These conditions are a frequent cause of elderlypeople's confinement to nursing homes and other protected environments.While they are more common among women than among men, at all ages,these conditions afflict significant numbers of both sexes. It is wellknown that many children past the usual age of toilet-training sufferfrom nocturnal enuresis, and that the elderly are quite likely todevelop bladder over-activity or urinary incontinence as they growolder. However, some studies have reported daily incontinence among asmany as 17% of young, apparently healthy, women. Thus, it is clear thatreliable and safe methods of treating bladder over-activity and urinaryincontinence are seriously needed.

[0002] Bladder over-activity and urinary incontinence can result fromvarious neurological disorders; such as Parkinson's Disease, multiplesclerosis, spinal cord injury, stroke, and Alzheimer's Disease. Bladderover-activity can also result from various disorders localized to thelower urinary tract; such as prostatitis, prostatodynia, urethritis,interstitial cystitis, urinary tract infection, outlet obstruction,benign prostate hyperplasia, radiation therapy of the pelvic viscera,diabetes, or vulvodynia. Bladder over-activity can also be idiopathic.

[0003] Thus, it is clear that bladder over-activity and urinaryincontinence are major disorders of today. It is believed to afflictapproximately 12 million people in the United States alone, and to occurin from 15 to 30% of the population over the age of 60. Its treatment atpresent is quite unsatisfactory.

[0004] The therapies currently used for certain conditions listed aboveoften do not resolve bladder over-activity and incontinence. Forexample, L-dopa treats the motor symptoms of Parkinson's disease, butcan actually exacerbate bladder over-activity. Likewise, surgicalremoval of the prostate and the use of alpha adrenergic receptorantagonists can improve urine flow and decrease residual urine, but thesymptoms of frequency, urgency, and nocturia often persist.

[0005] The mainstay therapy for treatment of bladder over-activity andincontinence are drugs that are muscarinic cholinergic receptorantagonists (“anticholinergics”) with varying degrees of calcium channelblocking activity. The only compounds prescribed in significantquantities are tolterodine and oxybutynin. Off-label use of tricyclicantidepressants, such as imipramine, which also exhibit significantanticholinergic properties is also practiced. These compounds work byblocking the excitatory effects of acetylcholine on the bladder smoothmuscle, thus suppressing bladder contractions and reducing bladderover-activity. Unfortunately, these compounds not only suppress bladderover-activity, but they also suppress normal bladder activity, whichresults in increases in residual urine, i.e., the bladder does not emptycompletely and the remaining urine provides a medium for bacterialgrowth and subsequent urinary tract infections. A potential increase inresidual volume is especially problematic for BPH patients who alreadyhave problems with residual urine due to obstruction of the urineoutlet, i.e., the urethra. Thus, anticholinergic drugs arecontraindicated for BPH patients. In addition, all of these“anticholinergics” cause undesirable side-effects typical ofanticholinergic drugs such as dry mouth, constipation, etc., and theefficacy of anticholinergic compounds is only partial.

[0006] Currently, there are no medicines indicated for the treatment ofstress urinary incontinence. Off-label use of sympathomimetics, such aspsuedoephidrine, is practiced, but the efficacy is questionable. Theonly therapies currently recognized by physicians are behavioralmodification, pelvic floor exercises, and surgery.

[0007] Over the last several years, various studies have implicated theneurotransmitter serotonin (5-hydroxytryptamine, 5HT) in control oflower urinary tract function. 5HT terminals and various receptorsubtypes are intimately associated with spinal cord areas that containafferent and efferent components of lower urinary tract neural controlcenters (Besson and Chaouch, Pain Headache, 9, 64-100 (1987); Y. Hosoya,et al., Exp. Brain Res., 86, 224-228, (1991); M. Kojima, et al., CellTissue Res., 229, 23-36 (1983); N. Rajaofetra, J. Comp. Neurol., 318,1-17 (1992); K. B. Thor, et al., Neuroscience, 55, 235-252 (1993)).Pharmacological and physiological studies have indicated that theprevailing effects of 5HT receptor activation on the urinary bladder areinhibitory. (M. J. Epsey, et al., Eur., J. Pharmacol., 221, 167-170(1992); Fakuda and Koga, Exp. Brain Res., 83,303-316 (1991); McMahon andSpillane, Brain Res., 234, 237-249 (1982); Steers and deGroat, Am. J.Physiol., R1441-1449 (1989); K. B. Thor, et al., Brain Res. Dev. BrainRes., 54, 35-42 (1990); Thor and Katofiasc, J. Pharmacol. Expt. Ther.,274, 1014-1024 (1996); and Thor et al., 1998).

[0008] It has been recognized that there are multiple types of 5-HTreceptors. These receptors have been classified as 5-HT₁, 5-HT₂, 5-HT₃,5-HT₄, 5-HT₅, 5HT₆ and 5-HT₇. The most heterogeneous of these classesappears to be 5-HT₁, subclassified as: 5-HT_(1A), 5-HT_(1B), and5-HT_(1D) (Hamon et al., Neuropsychopharmacol., 3(5/6), 349-360 (1990))and 5-HT_(1E) (Leonhardt et al., J. Neurochem., 53 (2), 465-471 (1989)).A human gene which expresses an additional 5-HT₁ subclass, 5-HT_(1F) wasisolated by Kao and coworkers (Proc. Natl. Acad. Sci. USA, 90, 408-412(1993)).

[0009] Thus, it is clear that there is an unmet medical need forpharmaceuticals that are effective for the treatment of bladderover-activity and urinary incontinence, and free from undesired sideeffects. The present invention provides such pharmaceuticals.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGS. 1A, IB, and IC—The effect of control infusion of saline,control infusion of acetic acid and after GR127935 during the infusionof acetic acid on the activity of external urethral sphincter EMG andbladder pressure.

[0011]FIGS. 2A, 2B, and 2C—The effect of the administration ofzolmitriptan on bladder capacity, bladder contraction frequency, andexternal urethral sphincter EMG activity.

[0012]FIGS. 3A, 3B, and 3C—The effect of the administration of GR127935on bladder capacity, bladder contraction frequency, and externalurethral sphincter EMG activity.

[0013]FIGS. 4A, 4B, and 4C—The effect of the administration of GR46611on bladder capacity, bladder contraction frequency, and externalurethral sphincter EMG activity.

[0014]FIGS. 5A, 5B, and 5C—The effect of the administration of LY217101on bladder capacity, bladder contraction frequency, and externalurethral sphincter EMG activity.

[0015]FIGS. 6A, 6B, and 6C—The effect of the administration of LY217101after WAY100635 on bladder capacity, bladder contraction frequency, andexternal urethral sphincter EMG activity.

[0016]FIGS. 7A, 7B, and 7C—The effect of the administration, in a singleexperiment, of LY217101, followed first by the administration ofWAY100635, and secondly by the administration of LY217101, on bladdercapacity, heart rate, bladder pressure, and external urethral sphincterEMG activity.

SUMMARY OF THE INVENTION

[0017] The present invention provides compounds of formula I:

[0018] wherein R¹ represents C₁-C₄ alkyl;

[0019] and the pharmaceutically acceptable salts and solvates thereof.

[0020] In accordance with the present invention, there is provided amethod of treating bladder over-activity or urinary incontinence in apatient in need of such treatment, comprising administering to thepatient an effective amount of a combined 5-HT_(1B) and 5-HT_(1D)receptor agonist.

[0021] The present invention also provides a method of treating bladderover-activity or urinary incontinence in a patient in need of suchtreatment, comprising administering to the patient an effective amountof a combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor agonist.

[0022] The present invention further provides a method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a 5-HT_(1B) receptor agonist in combination with a 5-HT_(1D)receptor agonist.

[0023] Additionally, the present invention provides a method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a 5-HT_(1A) receptor agonist in combination with a 5-HT_(1B)receptor agonist and 5-HT_(1D) receptor agonist.

[0024] Furthermore, the present invention provides a method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a compound of formula I.

[0025] According to another aspect, the present invention provides theuse of a compound of formula I, or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating bladderover-activity or urinary incontinence.

[0026] In addition, the present invention provides the use of a compoundof formula I, or a pharmaceutically acceptable salt thereof for treatingbladder over-activity or urinary incontinence.

[0027] Furthermore, the present invention provides a pharmaceuticalcomposition comprising an effective amount of a compound of formula Iand one or more pharmaceutically acceptable diluents or carriers.

[0028] The invention further provides a process for preparing a compoundof formula I

[0029] wherein R¹ represents C₁-C₄ alkyl, comprising sulfonylating acompound of the formula;

[0030] with a compound of the formula;

C₁-C₄alkylSO₂Lg;

[0031] wherein Lg is a suitable leaving group.

[0032] Furthermore, the invention provides a compound of the formula;

DETAILED DESCRIPTION OF THE INVENTION

[0033] As used herein the term “LY217101” refers to1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(see example 1 below).

[0034] As used herein the term “C₁-C₄ alkyl” refers to straight orbranched, monovalent, saturated aliphatic chains of 1 to 4 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, and t-butyl. It is understood that with regard tosubstituent R¹, methyl is preferred.

[0035] The present invention includes the hydrates and thepharmaceutically acceptable salts and solvates of the compound definedby formula I. The compound of this invention can possess a sufficientlybasic functional group, and accordingly react with any of a number ofinorganic and organic acids, to form a pharmaceutically acceptable salt.

[0036] The term “pharmaceutically acceptable salt” as used herein,refers to salts of the compound of formula I which are substantiallynon-toxic to living organisms. Typical pharmaceutically acceptable saltsinclude those salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are also known as acid addition salts. Such salts include thepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2-19 (1977) which are known to the skilled artisan.

[0037] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide,hydrobromide, iodide, acetate, propionate, decanoate, caprate,caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride,isobutyrate, caproate, heptanoate, propiolate, glucuronate, glutamate,propionate, phenylpropionate, salicylate, oxalate, malonate, succinate,suberate, sebacate, fumarate, malate, maleate, hydroxymaleate,mandelate, mesylate, nicotinate, isonicotinate, cinnamate, hippurate,nitrate, stearate, phthalate, teraphthalate, butyne-1,4-dioate,butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate,methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, phthalate, p-toluenesulfonate,p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate,phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate, hemi-tartrate,benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-napththalenesulfonate,1,5-naphthalenedisulfonate, mandelate, tartarate, and the like.Preferred pharmaceutically acceptable acid addition salts are thoseformed with mineral acids such as hydrochloric acid and hydrobromicacid, and those formed with organic acids such as maleic acid, oxalicacid and methanesulfonic acid. Preferred pharmaceutically acceptablesalts are hydrochloride, hydrobromide, oxalate, maleate,methanesulfonate, and hemi-tartrate. The most preferred pharmaceuticallyacceptable salt is hydrochloride.

[0038] It should be recognized that the particular counterion forming apart of any salt of this invention is usually not of a critical nature,so long as the salt as a whole is pharmacologically acceptable and aslong as the counterion does not contribute undesired qualities to thesalt as a whole. It is further understood that the above salts may formsolvates, or exist in a substantially uncomplexed form, such as theanhydrous form. As used herein, the term “solvate” refers to a molecularcomplex wherein the solvent molecule, such as the crystallizing solvent,is incorporated into the crystal lattice. When the solvent incorporatedin the solvate is water, the molecular complex is called a hydrate.Pharmaceutically acceptable solvates include hydrates, methanolates,ethanolates, acetonitrilates and the like.

[0039] The compound of formula I can be prepared by techniques andprocedures readily available to one of ordinary skill in the art, forexample by following the procedures as set forth in Scheme I. Allsubstituents, unless otherwise indicated, are previously defined. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

[0040] In Scheme I, step A, 3-nitrophenylacetic acid (1) is coupled withN-(α,α,α-trifluoro-m-tolyl)piperazine (2) under conditions well known inthe art to provide the amide (3). For example, 3-nitrophenylacetic acid(1) is dissolved in a suitable organic solvent, such as toluene andtreated with an excess of oxalyl chloride. The reaction is allowed tostir at room temperature for about 1 to 3 hours and then carefullyheated until an exotherm occurs. After the exotherm subsides, thereaction is heated at reflux for about 2 to 4 hours and thenconcentrated to provide the acid chloride. The acid chloride is thendissolved in a suitable organic solvent, such as acetone, and thesolution is added dropwise to a stirring solution of one equivalent ofN-(α,α,α-trifluoro-m-tolyl)piperazine (2), and one equivalent of asuitable base, such as sodium carbonate, in a suitable solvent mixture,such as water/acetone (1:1). The temperature is maintained below 30° C.After addition is complete, the reaction is stirred for about 16 hoursat room temperature. The amide (3) is then isolated by techniques wellknown in the art, such as extraction. For example, the acetone isessentially evaporated and the remaining aqueous is extracted with asuitable organic solvent, such as diethyl ether. The organic extractsare combined, washed with water, 2N HCl, brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide theamide (3).

[0041] In Scheme I, step B, amide (3) is reduced under standardconditions to provide the piperazine (4). For example, amide (3) isdissolved in a suitable organic solvent, such as tetrahydrofuran andthen added to a suitable reducing agent, such as borane. The reaction isstirred at room temperature for about 10 to 20 hours. It is then cooledto about 0° C. to 5° C. and treated with aqueous acid, such as 2N HCl.The organic solvent is then evaporated from the reaction mixture andexcess aqueous acid is added, such as 6N HCl. The mixture is then heatedat about 90° C. for about 1 hour. The piperazine (4) is then isolatedand purified by techniques well known in the art, such as extraction.For example, the cooled mixture is treated with a suitable aqueous base,such as sodium hydroxide solution to achieve a pH of greater than 12.The basified solution is then extracted with a suitable organic solvent,such as diethyl ether. The organic extracts are combined, washed withwater, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to provide piperazine (4).

[0042] In Scheme I, step C, piperazine (4) is further reduced underconditions well known in the art to provide the amine (5). For example,the piperazine (4) is dissolved in a suitable organic solvent, such asethanol, and the solution is treated with a catalytic amount of Raneynickel. The reaction mixture is then placed under hydrogen at about 60psi. The reaction is hydrogenated at room temperature for about 2 hours.The product is then isolated and purified using known techniques andprocedures. For example, the reaction mixture is filtered and thefiltrate is concentrated under vacuum. The crude residue is thenrecrystallized from a suitable organic solvent, such as hexanes toprovide the purified amine (5).

[0043] In Scheme I, step D, amine (5) is sulfonylated under standardconditions with a compound of formula C₁-C₄alkylSO₂Lg to provide theC₁-C₄alkylsulfonamide of formula I under conditions well known in theart. Lg represents a suitable leaving group, such as Cl, Br, and thelike. For example, amine (5) is dissolved in a suitable organic solvent,such as pyridine and cooled to less than 10° C. The solution is thentreated with about 1.25 equivalents of C₁-C₄alkylSO₂Lg, such asmethanesulfonyl chloride. The reaction is then stirred at roomtemperature for about 10 to 20 hours. The C₁-C₄alkylsulfonamide offormula I is then isolated and purified under using standard techniques,such as extraction and chromatography. For example, the above reactionmixture is poured into cold water and the mixture is extracted with asuitable organic solvent, such as diethyl ether. The organic extractsare combined, washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The crude residue isthen purified by flash chromatography on silica gel with a suitableeluent, such as methylene chloride/methanol to provide the purifiedC₁-C₄alkylsulfonamide of formula I as the free base.

[0044] The pharmaceutically acceptable salt of formula I is readilyprepared by one of ordinary skill in the art. For example, the free baseis dissolved in a suitable organic solvent, such as methanol or amixture of methanol/diethyl ether, and treated with an acid, such asoxalic acid or hydrochloric acid. The solvent is evaporated and theresidue is recrystallized from a suitable solvent such as ethylacetate/methanol to provide the pharmaceutically acceptable salt of thecompound of formula I.

[0045] Table I depicts the results of the binding affinity as a K₁ in nMor % displacement of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazineas compared to1-(2-p-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(see U.S. Pat. No. 3,170,926) at six serotonin receptors. TABLE IReceptor

5-HT_(1B) 1.7 nM 9.49 nM 5-HT_(1D) 1.2 nM 55.3 nM 5-HT_(1A) 0.95 nM 3.455-HT_(1E) 3876 nm  5% @ 1000 nM 5-HT_(1F) 32.3 nM 14% @ 1000 nM 5-HT₇103.8 nM 45

[0046] Table I reveals that1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehas a 56-fold higher affinity for the 5-HT_(1B) receptor than1-(2-p-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine.In addition, Table I reveals that1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehas a 45-fold higher affinity for the 5-HT_(1D) receptor than1-(2-p-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine.The above data supports the conclusion that1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehas surprising and unexpectedly high binding affinity for the 5-HT_(1B)and 5-HT_(1D) receptors as compared to the corresponding regioisomer,1-(2-p-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine.

[0047] The present invention provides a method of treating bladderover-activity or urinary incontinence in a patient in need of suchtreatment, comprising administering to the patient an effective amountof a combined 5-HT_(1B) and 5-HT_(1D) receptor agonist.

[0048] The term “combined 5-HT_(1B) and 5-HT_(1D) receptor agonist”, asit is used in the description of the present invention, is taken to meana compound which is a full or partial agonist at the 5-HT_(1B) and5-HT_(1D) receptors. A compound which is a partial agonist at the5-HT_(1B) and 5-HT_(1D) receptor must exhibit sufficient activity toincrease bladder capacity and sphincter EMG activity by at least 20%.While a partial agonist of any intrinsic activity may be useful for themethod of this invention, partial agonists of at least about 50% agonisteffect (E_(max)) are preferred and partial agonists of at least about80% agonist effect (E_(max)) are more preferred. Full agonists at the5-HT_(1B) and 5-HT_(1D) receptors are most preferred.

[0049] Suitable combined 5-HT_(1B) and 5-HT_(1D) receptor agonistsinclude, but are not limited to, RU24969, GR127935, eletriptan,zolmitriptan, naratriptan, rizatriptan, avitriptan, anpirtoline,alniditan,BMS-181885—(3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-methyl-3-cyclobuten-3-yl)amino-1H-indole),and all dimerizations of the above compounds.

[0050] The above-listed compounds are commercially available or arereadily prepared by one of ordinary skill in the art following knownprocesses and procedures, for example, see U.S. Pat. Nos. 4,196,209,5,340,810, 5,545,644, 5,466,699, 4,997,841, 5,298,520, 5,434,154,5,624,952, and 5,521,188.

[0051] In addition, the present invention provides a method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptoragonist.

[0052] The term “combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptoragonist”, as it is used in the description of the present invention, istaken to mean a compound which is a full or partial agonist at the5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptors. A compound which is apartial agonist at the 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor mustexhibit sufficient activity to increase bladder capacity and sphincterEMG activity by at least 20%. While a partial agonist of any intrinsicactivity may be useful for the method of this invention, partialagonists of at least about 50% agonist effect (E_(max)) are preferredand partial agonists of at least about 80% agonist effect (E_(max)) aremore preferred. Full agonists at the the 5-HT_(1A), 5-HT_(1B) and5-HT_(1D) receptors are most preferred.

[0053] Suitable combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptoragonists include, but are not limited to, the compound of Formula I andGR46611. GR46611 is readily prepared by one of ordinary skill in the artfollowing known processes and procedures, for example, see J. Med. Chem.(1996), 39(24) 4717-4726.

[0054] In another aspect, the present invention provides a method oftreating bladder over-activity or urinary incontinence in a patient inneed of such treatment, comprising administering to the patient aneffective amount of a 5-HT_(1B) receptor agonist, a 5-HT_(1D) receptoragonist, or a 5-HT_(1B) receptor agonist in combination with a 5-HT_(1D)receptor agonist.

[0055] More preferably, the present invention provides a method oftreating bladder over-activity or urinary incontinence in a patient inneed of such treatment, comprising administering to the patient aneffective amount of a 5-HT_(1B) receptor agonist in combination with a5-HT_(1D) receptor agonist.

[0056] The term “5-HT_(1B) receptor agonist”, as it is used in thedescription of the present invention, is taken to mean a compound whichis a full or partial agonist at the 5-HT_(1B) receptor. A compound whichis a partial agonist at the the 5-HT_(1B) receptor must exhibitsufficient activity to increase bladder capacity and sphincter EMGactivity by at least 20%. While a partial agonist of any intrinsicactivity may be useful for the method of this invention, partialagonists of at least about 50% agonist effect (E_(max)) are preferredand partial agonists of at least about 80% agonist effect (E_(max)) aremore preferred. A full agonist at the the 5-HT_(1B) receptor is mostpreferred.

[0057] Suitable 5-HT_(1B) receptor agonists include, but are not limitedto, SB-216641—(N-[3-(2-dimethylamino)ethoxy4-methoxyphenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1′-biphenyl)-4-carboxamide),see U.S. Pat. No. 5,801,170.

[0058] The term “5-HT_(1D) receptor agonist”, as it is used in thedescription of the present invention, is taken to mean a compound whichis a full or partial agonist at the 5-HT_(1D) receptor. A compound whichis a partial agonist at the the 5-HT_(1D) receptor must exhibitsufficient activity to increase bladder capacity and sphincter EMGactivity by at least 20%. While a partial agonist of any intrinsicactivity may be useful for the method of this invention, partialagonists of at least about 50% agonist effect (E_(max)) are preferredand partial agonists of at least about 80% agonist effect (E_(max)) aremore preferred. A full agonist at the 5-HT_(1D) receptor is mostpreferred.

[0059] Suitable 5-HT_(1D) agonists include, but are not limited to,BRL-15572—3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenyl-2-propanol),see Eur. J. Pharmacol., 331(2/3), 169-174 (1997)).

[0060] The term, “a 5-HT_(1B) receptor agonist in combination with a5-HT_(1D) receptor agonist,” as it is used in the description of thepresent invention, is taken to mean a first compound which is a full orpartial agonist at the 5-HT_(1B) receptor in combination with a secondcompound which is a full or partial agonist at the 5-HT_(1D) receptor.

[0061] Further, the present invention provides a method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administering to the patient an effectiveamount of a 5-HT_(1A) receptor agonist in combination with a 5-HT_(1B)receptor agonist and 5-HT_(1D) receptor agonist.

[0062] The term “5-HT_(1A) receptor agonist”, as it is used in thedescription of the present invention, is taken to mean a compound whichis a full or partial agonist at the 5-HT_(1A) receptor. A compound whichis a partial agonist at the the 5-HT_(1A) receptor must exhibitsufficient activity to increase bladder capacity and sphincter EMGactivity by at least 20%. While a partial agonist of any intrinsicactivity may be useful for the method of this inveniton, partialagonists of at least about 50% agonist effect (E_(max)) are preferredand partial agonists of at least about 80% agonist effect (E_(max)) aremore preferred. A full agonist at the 5-HT_(1A) receptor is mostpreferred.

[0063] Suitable 5-HT_(1A) agonists include, but are not limited to,8-OH-dipropyl-aminotetraline, ipsapirone (see U.S. Pat. No. 4,818,756),buspirone (see U.S. Pat. No. 3,717,634), flesinoxan (see U.S. Pat. No.4,833,142), urapidil (see U.S. Pat. No. 3,957,786), gepirone (see U.S.Pat. No. 4,423,049), A-74283—(+,−)trans-2-(4-(3a,4,4a,6a,7,7a-hexahydro-4,7-etheno-1Hcyclobut[f]isoindol-1,3-dionyl)-butyl)-9-methoxy-2,2,2a,4,5,9b-hexahydro-1H-benz[e]isoindol(see WO 90/06927),U-92016A—[(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole](see U.S. Pat. No. 5,650,427), U-89968E,(3,4-dichlorophenyl):4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)methyl]piperidin-1-yl:methanone,4-dichlorophenyl):4-[(6-azetidinopyridin-2-ylmethylamino)methyl]piperidin-1-yl:methanone, F11440—(4-methyl-2-[4-(4-(pyrimidin-2-yl)-piperazino)-butyl]-2H,4H-1,2,4-triazin-3,5-dione),and all dimerizations of the above compounds.

[0064] For purposes of the present invention, “a 5-HT_(1A) receptoragonist in combination with a 5-HT_(1B) receptor agonist and 5-HT_(1D)receptor agonist” is taken to mean at least two compounds which, incombination, are full or partial agonists at the 5-HT_(1A) receptor, the5-HT_(1B) receptor and the 5-HT_(1D) receptor. For example “a 5-HT_(1A)receptor agonist in combination with a 5-HT_(1B) receptor agonist and5-HT_(1D) receptor agonist” could be a compound having activity at the5-HT_(1A) receptor in combination with a compound having activity at the5-HT_(1B) and 5-HT_(1D) receptors. Alternatively, “a 5-HT_(1A) receptoragonist in combination with a 5-HT_(1B) receptor agonist and 5-HT_(1D)receptor agonist” could be a compound having activity at the 5-HT_(1A)and 5-HT_(1B) receptors in combination with a compound having activityat the 5-HT_(1D) receptor. It is to be appreciated that the invention ofthe present invention includes any combination that results in full orpartial agonist activity at the 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D)receptors.

[0065] It is to be appreciated that the compounds that have full orpartial agonist activity at the 5-HT_(1A), 5-HT_(1B) and/or 5-HT_(1D)receptors, as defined above, may have activity at additional receptors.For example, a compound which has full or partial agonist activity atthe 5-HT_(1B) and 5-HT_(1D) receptors may also have full or partialagonist activity at the 5-HT_(1F) receptor or non 5-HT receptors, suchas adrenergic or cholinergic receptors.

[0066] Table II depicts the results of the binding affinity as a K_(i)in nM or % displacement of the compound of formula I at six serotoninreceptors. TABLE II Binding and Functional Data in Cloned HumanSerotonin Receptors Structure 5-HT_(1A) 5-HT_(1B) 5-HT_(1D) 5-HT_(1E)5-HT_(1F) 5-HT₇ Formula 1

K_(j)EC₅₀E_(max)K_(b) .95 1.7 .9 88.2 1.2 .7 93.4 3876 32.3 161.5 95.5103.8 Agonist Agonist Agonist

[0067] Table II reveals that the compound of formula I is an agonist atthe 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptors.

[0068] Accordingly, the present invention also provides a method oftreating bladder over-activity or urinary incontinence in a patient inneed of such treatment, comprising administering to the patient aneffective amount of a compound of formula I.

[0069] The terms “treating” or “treat” as used herein include thegenerally accepted meaning which encompasses prohibiting, preventing,restraining, and slowing, stopping, or reversing progression, severity,of a resultant symptom. As such, the methods of this invention encompassboth therapeutic and prophylactic administration.

[0070] As used herein, the terms “bladder over-activity” and “detrusorover-activity” refer to activity of the urinary bladder that causes orpresents symptoms of urinary frequency, urinary urgency, nocturia,and/or urinary incontinence. The term “urinary frequency” as used hereinrefers to a need for frequent emptying of the bladder. The term “urinaryurgency” refers to an urgent sensation of an impending void that may notbe controllable. The term “nocturia” as used herein is defined asawakening frequently during sleep to void. The conditions associatedwith bladder over-activity include, but are not limited to, bladderhyperactivity, bladder hyperreflexia, unstable bladder, neurogenicbladder, uninhibited bladder contractions. For purposes of the presentinvention, it is understood that the terms “bladder” and “detrusor” areinterchangeable.

[0071] As used herein, the term “urinary incontinence” refers to theinvoluntary voiding of any quantity of urine resulting from bladderactivity by the patient from the patient's body.

[0072] The term “urge urinary incontinence” for purposes of thisinvention refers to the involuntary voiding of any quantity of urineresulting from bladder activity by the patient from the patient's body.Urge incontinence is caused by excessive intra-bladder pressure.

[0073] The term “stress urinary incontinence” for purposes of thepresent invention refers to involuntary voiding of any quantity of urineresulting from a weak urethral sphincter by the patient from thepatient's body. A weak urethral sphincter that allows the leakage orurine during a cough, laugh, or sneeze in the absense of bladderover-activity results in stress incontinence.

[0074] Urinary incontinence is a manifestation of the failure of controlof the muscles of the urinary sphincter and of the bladder. Thosemuscles are in balance, when the system is operating properly. Theurinary sphincter should be sufficiently strong to hold back thepressure exerted by the muscles of the bladder, except when the subjectconsciously relaxes the sphincter in order to urinate. Incontinenceresults when the pressure within the bladder is too great, as a resultof excessive force exerted by the muscles of the bladder or when theurinary sphincter is too weak to hold back the normal intra-bladderpressure. Incontinence is broadly classified as urge incontinence andstress incontinence. Patients often are seen with components of bothurge and stress incontinence, a condition that is referred to herein as“mixed urinary incontinence” or “mixed incontinence”. It is understoodthat urge incontinence, stress incontinence and mixed incontinence fallwithin the scope of the term urinary incontinence or incontinence.

[0075] The methods of the present invention are used to treat andcontrol bladder over-activity and urinary incontinence, either alone orin combination, in patients of any age in need of such treatment. Themethods of the present invention are used to treat and control urinaryincontinence of any one, or all of the stress, urge, and mixed types, inpatients of any age in need of such treatment. The cause of the bladderover-activity or urinary incontinence is not critical to the benefit ofthe present invention. For example, incontinence caused by deteriorationof the central nervous system, the peripheral nervous system, themuscles of the bladder or urethra, and infections of bladder or urethraare all effectively treated by the present method.

[0076] The types of bladder over-activity and urinary incontinence whichhave resulted from or have been caused by various neurologicaldisorders, such as Parkinson's disease, multiple sclerosis, spinal cordinjury, stroke, and Alzheimer's disease are effectively treated by thepresent method. Furthermore, bladder over-activity and incontinencewhich is caused by or has resulted from various disorders localized tothe lower urinary tract, such as prostatitis, prostatodynia, urethritis,detrusor instability, interstitial cystitis, urinary tract infection,outlet obstruction, benign prostate hyperplasia, diabetes, or vulvodyniaare effectively treated by the present method. Still further, bladderover-activity and urinary incontinence brought about by pelvic surgery,radiation therapy of the pelvis viscera, or anatomical changes in thegeometry of the bladder and urethra, urethral deterioration as a resultof cessation of estrogen production, and bladder hyperactivity are alleffectively treated. Finally, bladder over-activity and incontinencewhich are idiopathic are all treated by the method of the presentinvention.

[0077] It will be demonstrated by the examples that follow that themethods of the present invention have the ability to increase theeffective volume of the bladder, and simultaneously to increase thecontractility and nervous system control of the muscles which manage theurethra. Accordingly, it is clear that the present invention controlsboth bladder over-activity and incontinence, by increasing the effectivevolume of the bladder and decreasing involuntary muscular activityaround the bladder. Furthermore, the present invention controls stressincontinence by increasing control of the urethral sphincter andimproving the tone of the urethral musculature.

[0078] Adult female cats were anesthetized with alpha chloralose (50-75mg/kg i.v.) One catheter was inserted into the carotid artery formeasuring systemic blood pressure and heart rate. A second catheter wasinserted in the radial vein for administering drugs. Following a midlinelaparotomy, the bladder was cannulated through the dome to allowinfusion of fluids and recording of intravesical pressure. The urethraremained patent to allow expulsion of fluids during reflex micturition.

[0079] Transvesical cystometrograms (CMGs) were recorded by emptying thebladder, beginning infusion (0.5 ml/min) with saline, and noting thevolume at which fluid release and bladder contraction occurred (i.e.micturition). This volume is defined as bladder capacity. EMG activitywas recorded from the periurethral musculature with bipolar hookelectrodes placed within 0.5 cm of the urethral meatus via anintravaginal approach. After establishing bladder capacity and EMGactivity under conditions of saline infusion, the infusion cannula wasswitched to infuse 0.5% acetic acid solution and cystometry repeated.

[0080] Following cystometry, the bladder was allowed to continuouslyfill, which produced rhythmic bladder contractions accompanied by fluidrelease. During this time of rhythmic bladder activity, vehicle or drugwas administered. Within 5 minutes, the bladder was emptied; another CMGwas performed, and bladder capacity and EMG activity were againmeasured. The bladder was then continuously filled to produce rhythmiccontractions with fluid release, and the frequency of these rhythmiccontractions was measured over a fifteen minute period to record drugeffects on contraction frequency. This procedure was repeated withincreasing doses of drug to produce a cumulative dose response curve.

[0081] GR46611 and GR127935 were dissolved with addition of a few dropsof acetic acid into saline. All other drugs were dissolved in saline.

[0082] Under control conditions (FIG. 1A), large (30-50 cm H₂O), rapidincreases in intravesical pressure, i.e. micturition contractionsmediated by a central reflex pathway, were recorded after infusion ofapproximately 5 ml saline into an initially empty bladder. The volume atwhich these micturitions contractions occur define bladder capacity.Upon switching to infusion of acetic acid (FIG. 1B); bladder capacity,contraction amplitude, and contraction duration were reduced, while thecontraction frequency was increased. Very little peri-urethral EMGactivity was recorded during infusion of saline and decreased slightlyduring infusion of acetic acid (FIGS. 2 and 3). The small amount of EMGactivity that was recorded in control periods occurred during, orimmediately after, a bladder contraction and was composed of phasicbursts of activity (each burst lasting 150-300 msec) separated by short(150-350 msec) periods of quiescence.

[0083] Administration of either a combined 5-HT_(1B) and 5-HT_(1D)receptor agonist, such as zolmitriptan and GR127935, or a combined5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor agonist, such as GR46611 andLY217101 produced dose-dependent increases in bladder capacity (FIGS.2A, 3A, 4A and 5A). The increase in bladder capacity was not accompaniedby changes in the amplitude or duration of the contractions uponreaching micturition threshold volumes (FIGS. 1C and 7A). Administrationof zolmitriptan, GR127935, GR46611 and LY217101 also reduced thefrequency of micturition contractions (FIGS. 2B, 3B, 4B and 5B).Administration of zolmitriptan, GR127935, GR46611 and LY217101 alsoincrease external urethral sphincter (“EUS”) electromyographic (“EMG”)activity (FIGS. 1C, 2C, 3C, 4C, 5C and 7A).

[0084] WAY100635, a 5-HT_(1A) receptor antagonist, partially reversedthe hypotension, bradycardia, decrease in contraction frequency andincrease in EMG activity induced by the administration of the compoundof Formula I (FIG. 7B). Although administration of LY217101 after WAY100635 no longer produces hypotension, bradycardia or increase in EMGactivity, the administration of LY217101 after WAY100635 continued toreduce the frequency of micturition contractions and to increase bladdercapacity (FIGS. 6A, 6B, 6C and 7C).

[0085] The results show that administration of either a combined5-HT_(1B) and 5-HT_(1D) receptor agonist or a combined 5-HT_(1A),5-HT_(1B) and 5-HT_(1D) receptor agonist increases bladder capacity. Theincrease in bladder capacity indicates utility for the treatment ofbladder over-activity and incontinence.

[0086] Additionally, the results show that administration of either acombined 5-HT_(1B) and 5-HT_(1D) receptor agonist or a combined5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor agonist increases EUS EMGactivity. The increase in EMG activity indicates utility for thetreatment of stress urinary incontinence.

[0087] Finally, the results show that administration of either acombined 5-HT_(1B) and 5-HT_(1D) receptor agonist or a combined5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor agonist had no effect on themagnitude of the bladder contraction once it had reached micturitionoccurred as efficiently after treatment as it had before treatment. Thisis important in light of the fact that current bladder over-activity andincontinence medicines, primarily anticholinergics, cause decreasedefficiency of micturition and increases in residual urine due tocompromise of bladder contractile force.

[0088] As used herein the term “patient” refers to a mammal, such as arat, guinea pig, mouse, cat, dog or human. It is understood that thepreferred patient is a human.

[0089] Based on standard clinical and laboratory tests and procedures,an attending diagnostician, as a person skilled in the art, can readilyidentify those patients who are in need of treatment for bladderover-activity or urge urinary incontinence.

[0090] As used herein the term “effective amount” refers to the amountor dose of the agonist compound or agonist compounds of the presentinvention, such as a compound of formula I, which provide the desiredeffect in the patient under diagnosis or treatment.

[0091] The term “agonist compound” or “agonist compounds” as used hereinincludes, a combined 5-HT_(1B) and 5-HT_(1D) receptor agonist, acombined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptor agonist, a5-HT_(1B) receptor agonist in combination with a 5-HT_(1D) receptoragonist, and a 5-HT_(1A) receptor agonist in combination with a5-HT_(1B) receptor agonist and 5-HT_(1D) receptor agonist.

[0092] An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular agonist or agonists administered; themode of administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; the use ofconcomitant medication; and other relevant circumstances.

[0093] An effective amount of a compound of formula I is expected tovary from about 0.001 micrograms per kilogram of body weight per day(mg/kg/day) to about 100 mg/kg/day. Preferred amounts are expected tovary from about 0.001 mg/kg/day to about 10 mg/kg/day. Especiallypreferred amounts are expected to vary from about 0.01 mg/kg/day toabout 1 mg/kg/day.

[0094] It is to be appreciated that the agonist compounds of the presentinvention can be administered alone or in combination. For example, acombined 5-HT_(1B) and 5-HT_(1D) receptor agonist is administered alone.However, a 5-HT_(1B) receptor agonist in combination with a 5-HT_(1D)receptor agonist is administered as a combination.

[0095] Generally, a combination of the agonist compounds of the presentinvention is created by choosing a dosage of each agonist according tothe spirit of the above dosage guidelines and administering each agonistin any manner which provides effective levels of the two compounds inthe body at the same time. They may be administered together, in asingle dosage form, or may be administered separately.

[0096] It is particularly preferred, however, for the adjunctivecombination to be administered as a single pharmaceutical composition,and so pharmaceutical compositions incorporating a combination ofagonists are important embodiments of the present invention. Suchcompositions may take any physical form, which is pharmaceuticallyacceptable, but orally usable pharmaceutical compositions areparticularly preferred. Such adjunctive pharmaceutical compositionscontain an effective amount of each of the compounds, which effectiveamount is related to the daily dose of the compounds to be administered.Each adjunctive dosage unit may contain the daily doses of bothcompounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

[0097] In effecting treatment of a patient suffering from bladderover-activity or urinary incontinence, the agonist compounds of thepresent invention, such as the compound of formula I, can beadministered in any form or mode which makes the compound bioavailablein effective amounts, including oral and parenteral routes. For example,compounds of formula I can be administered orally, subcutaneously,percutaneously, intramuscularly, intravenously, transdermally,intranasally, rectally, and the like. Oral administration is generallypreferred.

[0098] One skilled in the art of preparing formulations can readilyselect the proper form and mode of administration depending upon theparticular characteristics of the agonist compound selected, the diseasestate to treated, the severity of the disease, and other relevantcircumstances. The route of administration may be varied in any way,limited by the physical properties of the drugs and the convenience ofthe patient and the caregiver.

[0099] It is to be appreciated that when the agonist compounds of thepresent invention are administered in combination, each agonist compoundmay be administered by a different route. For example, one of the drugsmay be administered by one route, such as oral, and the other may beadministered by a second route, such as transdermal.

[0100] The agonist compounds of the present invention, such as thecompound of formula I can be administered alone or in the form of apharmaceutical composition in combination with pharmaceuticallyacceptable carriers or excipients, the proportion and nature of whichare determined by the solubility and other chemical properties of thecompound selected, the chosen route of administration, and standardpharmaceutical practice. The agonist compounds of the invention, whileeffective themselves, may be formulated and administered in the form oftheir pharmaceutically acceptable salts for purposes of stability,convenience of crystallization, increased solubility, and the like.

[0101] In another embodiment, the present invention providescompositions comprising a compound of formula I in admixture orotherwise in association with one or more inert carriers. Thesecompositions are useful, for example, as a convenient means of makingbulk shipments, or as pharmaceutical compositions.

[0102] More particularly, the present invention provides apharmaceutical composition comprising an effective amount of a compoundof formula I and one or more pharmaceutically acceptable diluents orcarriers.

[0103] The pharmaceutical compositions are prepared in a manner wellknown in the pharmaceutical art. In making the compositions of thepresent invention, the active ingredient will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier, and maybe in the form of a capsule, sachet, paper, or other container. When thecarrier serves as a diluent, it may be a solid, semi-solid, or liquidmaterial which acts as a vehicle, excipient, or medium for the activeingredient. The compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols, ointments containing, for example, up to10% by weight of active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

[0104] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum,acacia, calcium phosphate, alginates, tragcanth, gelatin, calciumsilicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,magnesium stearate, and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents.Compositions of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

[0105] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 1 mg to about 500 mg, more preferablyabout 5 mg to about 300 mg (for example 25 mg) of the active ingredient.The term “unit dosage form” refers to a physically discrete unitsuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier, diluent, or excipient. The term “activeingredient” refers to, for example, a compound of formula I.

[0106] In general all of the compositions are prepared according tomethods usual in pharmaceutical chemistry. A group of typical formulaeof compositions will be mentioned below, but the principles of suchformulations are so well known that no detailed discussion will beprovided.

Formulation 1

[0107] Hard gelatin capsules are prepared using the followingingredients Quantity (mg/capsule) Active Ingredient  5 Starch, dried 445Magnesium stearate  10 Total 460 mg

Formulation 2

[0108] A tablet is prepared using the ingredients below: Quantity(mg/capsule) Active Ingredient  10 Cellulose, microcrystalline 640Silicon dioxide, fumed  10 Stearic acid  5 Total 665 mg

[0109] The components are blended and compressed to form tablets eachweighing 665 mg.

[0110] The following examples further illustrate the invention andrepresent a typical syntheses of the compounds of formula I as describedgenerally above. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. As used herein, thefollowing terms have the meanings indicated: “eq” refers to equivalents;“g” refers to grams; “mg” refers to milligrams; “L” refers to liters;“mL” refers to milliliters; “μL” refers to microliters; “mol” refers tomoles; “mmol” refers to millimoles; “psi” refers to pounds per squareinch; “min” refers to minutes; “h” refers to hours; “° C.” refers todegrees Celsius; “TLC” refers to thin layer chromatography; “HPLC”refers to high performance liquid chromatography; “δ” refers to part permillion down-field from tetramethylsilane; “THF” refers totetrahydrofuran; “de” refers to diasteromeric excess; “i-PrOH” refers toisopropyl alcohol; “EtOH” refers to ethanol; “MeOH” refers to methanol;and “DMF” refers to N,N-dimethylformamide;

EXAMPLE 1

[0111] Preparation of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazineoxalate.

[0112] Scheme I, step A: 36.2 g (0.2 mole) of 3-Nitrophenylacetic acid(1) was stirred in 400 mL toluene at ambient temperature while 87.0 mL(1.0 mole) of Oxalyl chloride was added dropwise. After the addition wascomplete, the reaction was stirred for 1 hour at ambient temperature.The solution was slowly heated until an exothermic reaction occurred(approx. 56° C.). The external heat source was then removed until thereaction subsided. Continued heating at reflux temperature (approx. 95°C.) for 2 additional hours. Evaporation of the solution gave the acidchloride intermediate as a viscous oil. This crude intermediate wasdissolved in 500 mL acetone and this solution added dropwise to astirred mixture containing: 21.2 g (0.2 mole) Sodium carbonate, 46.0 g(0.2 mole) N-(α,α,α-trifluoro-m-tolyl) piperazine (2), 250 mL water and250 mL acetone. The temperature was kept below 30° C. with occasionalcooling. This mixture was stirred at ambient temperature for 16 hours.The acetone was evaporated from the reaction mixture and the remainingsolution extracted with diethyl ether three times. The extracts werewashed consecutively with water, 2N HCl solution and brine. After dryingwith sodium sulfate and filtering, the solution was evaporated to 69.9 g(97%) of the amide (3) as a viscous oil which was sufficiently pure foruse in the next reaction.

[0113] Scheme I, step B: A solution of 69.7 g (0.19 mole) of amide (3)dissolved in 700 mL tetrahydrofuran (THF) was added dropwise to 380 mL(0.38 mole) of a 1M Borane/THF solution. The temperature rose to 30° C.during this addition. This resulting solution stirred at ambienttemperature for 16 hours. After cooling to 5° C., 216 mL of a 2N HClsolution was added dropwise. The THF was evaporated from the resultingsolution. Added 650 mL of a 6N HCl solution to the remaining residue andheated this mixture at approximately 90° C. for one hour. Cooled andbasified (pH>12) with a 5N sodium hydroxide solution. Extracted thismixture 3 times with diethyl ether. The extracts were washed with waterand brine. After drying over sodium sulfate and filtering, the solutionwas evaporated to provide 64.3 g of piperazine (4) as an orange oil. Theaddition of one equivalent of p-toluenesulfonic acid to an ethyl acetatesolution of the above oil precipitated the tosylate salt.Recrystallization of this salt from ethanol provided 51.3 g (49%) ofyellow plates. mp 215-217° C. Anal. C,H,N.

[0114] Scheme I, step C: A solution of 19.0 g (0.05 mole) of piperazine(4), as the free base, in 225 mL ethanol was hydrogenated over 2.5 g ofRaney nickel at 60 PSI and ambient temperature for 2 hours. The solutionwas filtered and then evaporated to a solid. Recrystallization fromhexanes provided 10.4 g (59%) of the amine (5) as colorless crystals. mp70°-72° C. Anal. C,H,N. ¹H NMR (DMSO-d₆): δ 2.45-2.65 (m, 8H). 3.17-3.27(m, 4H), 4.93 (s, 2H), 6.32-6.45 (m, 3H), 6.85-7.45 (m, 5H).

[0115] Alternatively, Scheme I, Step C can be performed as follows:Piperazine (4) was dissolved in ethanol (100%, 60 mL) and divided infour portions (3×30 mL and 1×15 mL). Each of the portions were furtherdissolved with ethanol (100%, 100 mL), and Pd/C (10%, 1.5 g for the1^(st) three and 1.0 g for the last portion) was added. The resultingsolution was placed under H₂ (60 psi) with additional H₂ added as neededto maintain 60 psi throughout the reduction. H₂ was consumed for 20.5,21.5, 17.5, and 4 h for each portion respectively. The reaction wasmonitored by positive ion mass spectroscopy until completion. Theportions were filtered through Celite® and rinsed with absolute ethanol.The portions were combined and concentrated to an oil under vacuum, toyield amine (5) (52.27 g, 99%).

[0116] Scheme I, step D: To a cold solution (<10° C.) of 1.4 g (4.0mmole) of amine (5) dissolved in 12.5 mL pyridine, was added dropwise0.38 mL (5.0 mmole) of methanesulfonyl chloride. The resulting solutionwas stirred at ambient temperature for 16 hours. The solution was pouredonto 60 mL cold water and extracted 3 times with diethyl ether. Theextracts were washed with water and brine. After drying over sodiumsulfate and filtering, the solution was evaporated to 2.13 g of anorange oil. Flash chromatography (dichloromethane/methanol, 100/3,silica gel) provided 1.83 g of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine.

[0117] Alternatively, Scheme I, Step D can be performed as follows:Amine (5) (47.25 g. 0.135 mol) in anhydrous pyridine (420 mL) was cooledto 5° C. Methanesulfonyl chloride (13 mL, 0.169 mol) was added dropwiseover 30 min while maintaining 5° C. The solution was allowed to warm toambient temperature and stirred for 16 h. The solution was split intotwo portions (250 mL) and extracted separately. Each portion was pouredinto H₂O (1 L, 0° C.) and extracted with Et₂O (250 ML, ×3). The combinedEt₂O layers were washed twice with H₂O and brine. The washed Et₂O layerswere dried over Na₂SO₄. The separated portions were recombined, and thesolvent was removed under vacuum to yield an oil. The oil was treated 3times with toluene (250 mL) and dried under vacuum to help removeresidual pyridine. Crude1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinewas obtained (55.9 g, 97%).

[0118] The crude1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinewas split into 4 batches and flash chromatographed on four silica gelcolumns. The 1^(st) column of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(9.95 g) and silica gel (550 g) was eluted with a gradient of MeOHrunning from 1% to 5%, with 0.1% NH₄OH, the balance being methylenechloride. The 2^(nd) column of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(10.5 g) and silica gel (0.55 kg) was eluted with methylene chloride:MeOH: NH₄OH (96.5:3:0.5). The third and fourth columns were packed withsilica gel (1.4 kg) and were loaded with1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(14.64 g and 20.03 g). The third column had a gradient of 3% to 5% MeOHand the fourth was run with a gradient of 3.5% to 4% MeOH, both with0.5% NH₄OH, and the remainder being CH₂Cl₂. The columns were followed byTLC with a mobile phase of with methylene chloride: MeOH:NH₄OH (94:5:1),and visualized with UV (254 nm) and ninhydrin stain. The fractions ofgreater than 99% purity were combined to give1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(16.46 g).

[0119] Formation of the oxalate salt and recrystallization from ethylacetate/methanol gave 1.66 g (80%) of the final title compound,1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazineoxalate, as colorless crystals. mp 164° C. Anal. C,H,N. ¹H NMR(DMSO-d₆): δ 6 2.85-3.15 (m, 8H), 3.0 (s, 3H), 3.35-3.50 (m, 4H),7.0-7.5 (m, 8H), 9.73 (br s, 1H).

Example 1a Preparation of1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehydrochloride

[0120]1-(2-m-Methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazine(99%, 9.09 g, 21.3 mmol) was dissolved in minimal anhydrous diethylether and treated with one equivalent of HCl (1 M in Et₂O, 21.3 mL) andstirred. The resulting crude solid was taken to dryness under vacuum,then dissolved in minimal hot MeOH and allowed to slowly cool. Thesolution was further cooled to −10° C. before filtering. The filter cakewas washed with ice-cold methanol and allowed to dry, yielding anoff-white powder (5.50 g). The power was redissolved in minimal hot MeOHand allowed to cool to ambient temperature. The crystals were cooled to−10° C. and filtered. The filter cake was washed with cold MeOH andallowed to dry, yielding1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehydrochloride (4.50 g, 45%): mp 198-199° C.; IR (KBr) 1606 cm⁻¹; ¹H NMR(d₆-DMSO, 250 MHz, 6 mg/mL) δ 10.85 (bs, 1H), 9.78 (s, 1H), 7.47 (t,1H), 7.31 (m, 3H), 7.06 (m, 4H), 3.98 (d, 2H), 3.63 (d, 2H), 3.15 (m,8H), 2.99 (s, 3H); Anal. Calcd for C₂₀H₂₄F₃N₃O₂S.HCl: C 51.78; H, 5.43;N, 9.06. Found: C, 51.69; H, 5.53; N, 8.94.

We claim:
 1. A compound of the formula:

wherein R¹ represents C₁-C₄ alkyl; and the pharmaceutically acceptablesalts and solvates thereof.
 2. A compound according to claim 1 whereinR¹ is methyl.
 3. A compound according to claim 1 which is1-(2-m-methanesulfonamidophenylethyl)-4-(m-trifluoromethylphenyl)piperazinehydrochloride.
 4. A method of treating bladder over-activity or urinaryincontinence in a patient in need of such treatment, comprisingadministrating to the patient an effective amount of a combined5-HT_(1B) and 5-HT_(1D) receptor agonist.
 5. A method of treatingbladder over-activity or urinary incontinence in a patient in need ofsuch treatment, comprising administrating to the patient an effectiveamount of a combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptoragonist.
 6. A method of treating bladder over-activity or urinaryincontinence in a patient in need of such treatment, comprisingadministering to the patient an effective amount of a 5-HT_(1B) receptoragonist in combination with a 5-HT_(1D) receptor agonist.
 7. A method oftreating bladder over-activity or urinary incontinence in a patient inneed of such treatment, comprising administering to the patient aneffective amount of a 5-HT_(1A) receptor agonist in combination with a5-HT_(1B) receptor agonist and 5-HT_(1D) receptor agonist.
 8. A methodof treating bladder over-activity or urinary incontinence in a patientin need of such treatment, comprising administering to the patient aneffective amount of a compound of the formula:

wherein R¹ represents C₁-C₄ alkyl; or the pharmaceutically acceptablesalts or solvates thereof.
 9. A method of claim 8 wherein the urinaryincontinence is urge urinary incontinence.
 10. A method of claim 8wherein the urinary incontinence is stress urinary incontinence.
 11. Amethod of claim 8 wherein the urinary incontinence is mixed urinaryincontinence.
 12. A pharmaceutical composition comprising an effectiveamount of a compound as claimed in any one of claims 1 to 3, and one ormore pharmaceutically acceptable diluents or carriers.
 13. A compoundaccording to any of claims 1 to 3, or a pharmaceutically acceptable saltthereof, for use as a pharmaceutical.
 14. The use of a compoundaccording to any of claims 1 to 3, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for treating bladderover-activity or urinary incontinence.
 15. The use of a combined5-HT_(1B) and 5-HT_(1D) receptor agonist, for the manufacture of amedicament for treating bladder over-activity or urinary incontinence.16. The use of combined 5-HT_(1A), 5-HT_(1B) and 5-HT_(1D) receptoragonist, for the manufacture of a medicament for treating bladderover-activity or urinary incontinence.
 17. The use of a 5-HT_(1B)receptor agonist in combination with a 5-HT_(1D) receptor agonist forthe manufacture of a medicament for treating bladder over-activity orurinary incontinence.
 18. The use of a 5-HT_(1A) receptor agonist incombination with a 5-HT_(1B) receptor agonist and 5-HT_(1D) receptoragonist for the manufacture of a medicament for treating bladderover-activity or urinary incontinence.